Engineered Immune Cells Mediator Complex Subunit Reduction
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Solution Overview
Problem
Current adoptive T cell therapies, such as CAR-T cell therapy, face challenges in effectively targeting and treating solid tumors due to barriers like dense stroma, immunosuppressive tumor microenvironments, and tumor heterogeneity, which limit the migration, persistence, and efficacy of therapeutic T cells.
Innovation Solution
Engineered immune cells with reduced expression levels of mediator complex subunits, such as MED12 or CCNC, are generated using nucleic acids and polypeptides to enhance their effector functions, including increased cytokine production and anti-tumor cytotoxicity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If CAR-T cells are used to treat solid tumors, then anti-tumor specificity is improved, but migration through dense stroma and tumor microenvironment is hindered
Solution Approach 1:
The patent modifies the physical and chemical parameters of CAR-T cells by altering mediator complex subunit expression levels. Specifically, reducing expression of subunits such as MED12, CCNC, or MED13 changes the cellular parameters to enhance migration capability through dense stroma while preserving anti-tumor specificity through maintained CAR function
2Reliability
If CAR-T cells are administered to treat cancer, then therapeutic efficacy is improved, but persistence in tumor microenvironment is reduced
Solution Approach 1:
The patent changes cellular parameters by modulating mediator complex subunit expression to enhance CAR-T cell persistence. Reducing subunits like MED12 or CCNC alters cellular metabolism and survival mechanisms, enabling prolonged persistence in the tumor microenvironment while maintaining therapeutic efficacy through sustained anti-tumor activity
3Reliability
If CAR-T cells are used to target tumor cells, then cytolytic activity is improved, but proliferation in response to CAR antigen is limited
Solution Approach 1:
The patent modifies cellular parameters by adjusting mediator complex subunit expression to enhance proliferation. Reducing subunits such as MED13 or CCNC removes repressive effects on cell cycle progression, thereby increasing CAR-T cell proliferation in response to CAR antigen stimulation while preserving high cytolytic activity against tumor cells
Data Source
AI summary
The present disclosure generally relates to, inter alia, recombinant immune cells that have been engineered to express reduced levels of one or more subunits of the mediator complex, and particularly relate to engineered immune cells exhibiting enhanced effector functions. Also provided are methods for generating engineered immune cells with enhanced effector function, pharmaceutical compositions the same, as well as methods and kits for the prevention and/or treatment of a health condition in subjects in need thereof.